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Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1.

Nature medicine (2016-03-15)
Jean-Sébastien Joyal, Ye Sun, Marin L Gantner, Zhuo Shao, Lucy P Evans, Nicholas Saba, Thomas Fredrick, Samuel Burnim, Jin Sung Kim, Gauri Patel, Aimee M Juan, Christian G Hurst, Colman J Hatton, Zhenghao Cui, Kerry A Pierce, Patrick Bherer, Edith Aguilar, Michael B Powner, Kristis Vevis, Michel Boisvert, Zhongjie Fu, Emile Levy, Marcus Fruttiger, Alan Packard, Flavio A Rezende, Bruno Maranda, Przemyslaw Sapieha, Jing Chen, Martin Friedlander, Clary B Clish, Lois E H Smith
ZUSAMMENFASSUNG

Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy-consuming photoreceptors depend on glucose. Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid. In the retinas of Vldlr(-/-) mice with low fatty acid uptake but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr(-/-) photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr(-/-) retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD), which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.

MATERIALIEN
Produktnummer
Marke
Produktbeschreibung

Sigma-Aldrich
Anti-β-Actin-Antikörper, Maus monoklonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anti-Glucose-Transporter GLUT-3-Antikörper, CT, serum, Chemicon®